Structure of class B GPCR corticotropin-releasing factor receptor 1

Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism. Approximately 30% of known drugs target G protein-coupled receptors (GPCRs), but all the published structures of GPCRs to date are from the class A family of GPCRs; here the first X-ray crystal structure of a member of the class B family of GPCRs, the human corticotropin-releasing factor receptor 1, is determined. Two class B human GPCR receptors G-protein-coupled receptors (GPCRs) are membrane proteins that act as sensors for a broad range of extracellular signals, including photons, ions, small organic molecules and even entire proteins. Approximately a third of known drugs target GPCRs. Until now all the published structures of GPCRs have been from class A GPCRs. In this issue of Nature two groups independently report the crystal structures of two receptors of the B family, the second largest of four family divisions based on primary sequence and pharmacology. Hollenstein et al . solved the structure of human corticotropin-releasing factor receptor 1. This GPCR binds to corticotropin-releasing hormone, a potent mediator of endocrine, autonomic, behavioral and immune responses to stress. In all known class A GPCRs, the ligand-binding sites are close to the extracellular boundaries of the receptors; in this GPCR, the antagonist (CP-376395) binds in a hydrophobic pocket located in the cytoplasmic half of the V-shaped receptor. Siu et al . solved the X-ray crystal structure of the human glucagon receptor. This GPCR binds to the glucagon peptide, which triggers the release of gluco